Alpha-substituted 1-naphthylacetic acids



United States Patent 3,385,852 u-SUBSTITUTED i-NAPHTHYLACETIC ACIDSSilvano Casadio, Milan, Italy, assignor to Istituto de Angeli S.p.A.,Milan, Italy, a corporation of Italy No Drawing. Continuation-impart ofapplication SeraNo. 364,792, May 4, 1964. This application Apr. 23,1965, Ser. No. 450,4?6

Claims priority, application Great Britain, May 14, 1963, 19,159/63;Aug. 7, 1964, 32,300/64; Oct. 1, 1964, 40,025/ 64; Oct. 12, 1964,41,578/64 8 (Iiaims. (Cl. 260-246) ABSTRACT OF THE DISCLQSURE Thepresent application is directed to naphthylacetic acid derivatives andin particular to a,ot-disubstituted naphthylacetic acids. The compoundsof the invention fall within two distinct categories, that is, the shortchain a,a-disubstituted naphthylacetic acids where the short chainsubstituent group is represented by the grouping Cl-I CH X, wherein Xrepresents morpholino, piperidino or the grouping where each of R and Rrepresent an alkyl group of from 1 to 6 carbon atoms or benzyl. Thecompounds of the second category are the long-chain a,a-disubstitutednaphthylacetic acids which are characterized by having on the a-carbonat least one substituent represented by the grouping (CH X, wherein X isas above defined and n represents an integer of from 3 to 5. In eachcategory, the second a-substituted substituent may be an alkyl of from 1to 6 carbon atoms or a grouping similar to that represented by the CI-ICH X on the short chain compounds and the (CH -X in the long chaincompounds. The compounds of the invention exhibit various therapeuticproperties which make them particularly valuable.

This is a continuation-in-part of US. application Ser. No. 364,792 filedon May 4, 1964 and now US. Patent No. 3,344,146 whose disclosure isaccordingly incorporated herein by reference.

This invention relates to new tit-substituted l-naphthylacetic acidshaving valuable pharmacological properties.

It is an object of the present invention to provide u-substitutedl-naphthylacetic acids having valuable antipyretic (and in most casesalso anti-inflammatory) activity which may in addition, dependent on theexact structure, have chloretic or hypoglycemic activity.

It is a still further object of the present invention to providetit-substituted l-naphthylacetic acids having useful hypoglycemicactivity coupled with a relatively low toxicity.

These and other objects are fully attained by the present invention.

According to the present invention, there are provided short-chaina-substituted l-naphthylacetic acids of the general formula COOH inwhich R represents the group 3,385,852 Patented May 28, 1968 (wherein Rand R which may be the same or different, each represents an alkyl oraralkyl group or R and R together with the adjacent nitrogen atomrepresent a heterocyclic group which may contain a further hetero atom);and R represents a hydrogen atom, an alkyl group or any group which maybe represented by R and non-toxic salts thereof. The non-toxic salts maybe salts formed with acids or bases. The term short chain is used hereinin relation to compounds of Formula I to designate such compounds inwhich the alkyl radical of the a-aminoalkyl group contains only twocarbon atoms.

It will be appreciated that compounds of the Formula I in which R and Rrepresent different groups contain an asymmetric carbon atom. Opticalisomers of such compounds as well as racemic mixtures thereof areincluded within the scope of the present invention.

These short-chain tit-substituted l-naphthylacetic acids according tothe invention have valuable antipyretic activity and, in most cases,also have anti-inflammatory activity. In addition, dependent on theirexact structure the compounds may have choleretic or hypoglycemicactivity. Moreover they in general have a relatively low toxicity.

In compounds of the Formula I in which R R and/ or R represent alkylgroups, they preferably represent lower alkyl groups containing from 1to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl,isobutyl, amyl and/or hexyl groups. Where R or R represents an aralkylgroup, it preferably represents a benzyl group. Where R and R togetherwith the nitrogen atom to which they are bonded, represent aheterocyclic group, they preferably represent a saturated heterocyclicgroup such as, for example, a morpholino or piperidino group. Theheterocyclic group may if desired, as in the case of a morpholino group,contain a further hetero atom.

The non-toxic acid addition salts of compounds of Formula I may beformed both with organic and inorganic acids. Preferred non-toxic acidaddition salts include, for example, hydrochlorides, hydrobromides,sulphates, formates, acetates, citrates, tartrates, maleates andcyclohexyl sulphamates. The salts with bases include salts formed bothwith organic and inorganic bases.

As stated above, the short-chain zit-substituted l-naphthylacetic acidsof Formula I as defined above in general possess valuable antipyreticactivity and, in most cases, also have anti-inflammatory activity. Inaddition, the compounds may have choleretic or hypoglycemic activity.The compound a methyl-a-(Z-rnorpholinoethyl)-1-naphthylacetic acid is ofparticular interest in view of its choleretic activity which isassociated with a low toxicity; the LD of this compound, administeredorally, is 5,000 mg./l:g. Moreover, the compoundsa-isopropyl-ot-(Z-dicthylarninoethyl)-1-naphthyl-acetic acid anda-isOpropyl-a-(Z-methylethylaminoethyl)-1-naphthylacetic acid have agood hypoglycemic activity coupled with low toxicity; the LD of thesecompounds, administered orally, is 4,000 mg./kg. and about 2,500 mg./kg. respectively.

The short-chain u-substituted l-naphthylacetic acids of Formula I asdefined above may be incorporated into pharmaceutical compositionscomprising as active ingredient at least one of the tat-substitutedl-naphthylacetic acids in association with a pharmaceutical carrier orexcipient. The pharmaceutical compositions may take the same form as thepharmaceutical compositions described above containing a-substitutedl-naphthylacetamides. The compositions containing a-substitutedl-naphthylacetic acids are advantageously formulated as dosage units,each dosage unit being adapted to supply a single dose of the activeingredient. Each dosage unit may conveniently contain CO OH Rr-C-Ra inwhich R represents the group (wherein R and R which may be the same ordifferent, each represents an alkyl group or R and R together with theadjacent nitrogen atom represent a heterocyclic group which may containa further hetero atom, and n represents an integer from 3 to 5); and Rrepresents an alkyl group or any group which may be represented by R andnon-toxic salts thereof. The non-toxic salts may be salts formed withacids or bases. The term long chain is used herein in relation tocompounds of Formula I to designate such compounds in which the alkylradical of the a-aminoalkyl group contains over two carbon atoms.

It will be appreciated that the long-chain oc-SllbStitutedl-naphthylacetic acids in which R and R represent different groupscontain an asymmetric carbon atom. Optical isomers of such compounds aswell as racemic mixtures thereof are included within the scope of thepresent invention.

The long-chain rat-substituted l-naphthylacetic acids have valuablepharmacological properties. In particular, the compounds in generalpossess useful hypoglycemic activity coupled with a relatively lowtoxicity.

In long-chain compounds of the Formula I in which R R and/ or Rrepresent alkyl groups, they preferably rep-resent lower alkyl groupscontaining from 1 to 6 carbon atoms e.g. methyl, ethyl, propyl,isopropyl, butyl, sec. butyl, amyl and/or hexyl groups. Where R and Rtogether with the adjacent nitrogen atom to which they are bonded,represent a heterocyclic group, they preferably represent a saturatedheterocyclic group such as, for example, a pyrrolidino, pipe-ridino ormorpholino group.

The non-toxic acid addition salts of long-chain compounds of Formula Imay be formed both with organic and inorganic acids. Preferred non-toxicacid addition salts include, for example, hydrochlorides, hydrobromides,sulphates, formates, acetates, citrates, tartrates, maleates, cyclohexylsulphamates, methanesulphonates and ethanedisulphonates. The salts withbases include salts formed both with organic and inorganic bases.

As stated above, the long-chain a-substituted l-naphthylacetic acidsaccording to the invention have valuable hypoglycemic activity coupledwith relatively low toxicity. Particularly useful compounds according tothe invention by virtue of their espeially favourable activity andtoxicity properties are age: di(3 dimethylaminopropyl)-l-naphthylaceticacid and a,a-di(3-diethylaminopropyl)-1-naphthylacetic acid (LD uponoral administration of 4,000 and 5,000 mg./ kg. respectively).

The long-chain Ot-SilbSiiilliGd l-naphthylacetic acids of Formula I maybe incorporated into pharmaceutical compositions for oral administrationcomprising as active ingredient at least one of the long-chaina-substituted l-naphthylacetic acids in association with apharmaceutical carrier or excipient. These pharmaceutical compositionsmay take the same form as the pharmaceutical compositions suitable fororal administration described above and containing Ot-SUbStltlliCdl-naphthylacetamides. The compositions containing long-chaina-substituted l-naphthylacetic acids are advantageously formulated asdosage units, each dosage unit being adapted to supply a single dose ofthe active ingredient. Each dosage unit may conveniently contain 100 to1,000 mg. and preferably 200 to 600 mg. of the active ingredient.Examples of dosage unit forms are tablets, capsules, dragees and pills.

The short chain and longchain a-substituted lnaphthylacetic acids (inwhich R is other than hydrogen) are preferably prepared by a processwhich comprises reacting an amide of the formula CONH:

with nitrous acid or nitrous anhydride. In one particularly convenientmethod of carrying out this process, the nitrous acid is prepared insitu in the reaction mixture by reaction of an alkyl nitrite, forexample butyl, isoamyi or octyl nitrite, with a strong acid, for examplehydrochloric, hydrobromic or sulphuric acid. The reaction isadvantageously carried out in the presence of an organic solvent suchas, for example, glacial acetic acid.

In one particularly conventient method according to the invention,isoamyl nitrite is added, at room temperature, to a solution of an amideof Formula II in glacial acetic acid, which solution has been previouslysaturated with gaseous hydrochloric acid. The mixture is maintained atroom temperature for l to 4 hours and is then heated for 6 to 18 hoursat a temperature ranging from C. to the reflux temperature of themixture. Where compounds of the Formula II in which the groups R and Rhave a particularly pronounced steric hindrance effect are concerned,the above reaction procedure may require repeating a number of timesuntil a sample of the reaction product, after removal of solvent, iscompletely soluble in a 10% aqueous solution of NaOH; repetition of theprocedure from 2 to 6 times in general will be sufiicient to completethe reaction and yield a pure product.

Short-chain a-substituted l-naphthylacetic acids of the Formula I (inwhich R represents hydrogen), may be prepared by a process whichcomprises hydrolysing a nitrile of the formula The hydrolysis isconveniently carried out under acid conditions, preferably in thepresence of a strong aqueous acid e.g. a strong mineral acid such assulphuric acid. In one preferred process, the hydrolysis is effected inthe presence of a strong mineral acid and in addition a liquidcarboxylic acid, for example glacial acetic acid. A mixture ofconcentrated sulphuric acid, glacial acetic acid and water is especiallyeffective. About equal proportions by volume of the mineral acid andliquid carboxylic acid are preferably used and, in a particularlyconvenient process, the quantities by volume of water and each of thetwo acids used for the hydrolysis are substantially equal. Thehydrolysis is conveniently effected at elevated temperatures,advantageously at the reflux temperature of the reaction mixture.

The nitriles of Formula IV useful as starting materials in theabove-described process according to the invention may be prepared asdescribed in co-pending U.S. application Ser. No. 323,259, filed Nov.13, 1965, now abandoned.

Both the short-chain and long-chain (Jr-substituted l-naphthylaceticacids of the Formula I prepared as described above are convenientlyseparated from the reaction mixture in the form of their acid additionsalts e.g. hydrochlorides. They may be purified in any convenient way,for example by crystallisation from a suitable solvent or mixture ofsolvents. The hydrochlorides of compounds of the Formula I are ingeneral White crystalline solids soluble in water and also in aqueoussolutions of alkali (with formation of the corresponding base salts),slightly soluble in ethanol and propanol but practically insoluble inbenzene, ether, petroleum ether and hexane.

Acid addition salts, e.g. the hydrochlorides of compounds of the FormulaI, may be converted into the corresponding free amino acids by treatmentwith an equivalent of a base. The free amino acids of Formula I thusobtained are in general white crystalline solids soluble in aqueous acidand alkali solutions with formation of the corresponding salts.

The free amino acids of Formula I may be converted to further salts withacids or bases by treatment with the equivalent amount of acid or base.

The following examples illustrate the preparation of tat-substitutedl-naphthylacetic acids (and salts thereof) according to the inventionand also pharmaceutical compositions containing such compounds as activeingredients:

Example 1 A stream of dry hydrochloric acid is slowly bubbled, for oneand a half hours and at room temperature, through an externally cooledsolution of 40 g. of a-isopropyl-u-(Z-dimethylaminoethyl)-1-naphthylacetamide in 200 ml. of glacial aceticacid. 50 ml. of freshly distilled isoamyl nitrite are then added during2 hours and with stirring. The bright red solution thereby obtained ismaintained for a further two hours, at room temperature and then for 8hours at 100 C. The solvent is thereafter distilled ofi from thereaction mixture at 50 C. in vacuo, the residue disintegrated with etherand the solid thus formed crystallised from ethanokligroin (3: 1). Thea-isopropyl-a- (Z-dimethylaminoethyl)-1-naphthylacetic acidhydrochloride thereby obtained is a white crystalline solid melting at227-228 C.

Analysis.For c gHgsogNcl. Found, percent: C, 68.15; H, 7.79; N, 4.08;CI, 10.32. Calc., percent: C, 67.93; H, 7.80; N, 4.17; Cl, 10.52.

The following compounds are obtained by a method analogous to thatdescribed above:

a-methyl-a-(Z-dimethylaminoethyl)-1-naphthylacetic acid hydrochlorideM.P. 257 C. (decomp.) (crystallized from 95% ethanol).

Analysis.--For C H O NCI. Found, percent: C, 65.95; H, 7.11; N, 4.38;Cl, 11.41. Calc., percent: C, 66.33; H, 7.20; N, 4.45; Cl, 11.52.

a-ethyl-u-(Z-dimethylaminoethyl) -1-naphthylacetic acid hydrochlorideM.P. 236-237 C. [crystallized from ethanol-ligroin (3:1)].

Analysis.-For C H O NCl. Found, percent: C, 66.95; H, 7.51; N, 4.29; Cl,10.94. Calc., percent: C, 67.17; H, 7.52; N, 4.35; Cl, 11.02.

ec-secbutyl-a- (2-dimethylaminoethyl) -1-naphthylacetic acidhydrochloride M.P. 208-209 C. (decomp.) (crystallized from isopropanol).

Analysis.--For C H O NCl. Found percent: C, 68.83; H, 7.93; N, 4.04; Cl,9.96. Calc., percent: C, 68.65; H, 8.07; N, 4.00; Cl, 10.13.

a t-di-(2-dimethylaminoethyl)-1-naphthylacetic acid dihydrochloride M.P.227.5-229 C. (decomp.) [crystallized from ethanol-ligroin (1:1)].

Analysis.For CzgHgoOzNgClg. Found, percent: C,

6 59.20; H, 7.67; N, 6.86; Cl, 17.70. Calc., percent: 59.84; H, 7.53; N,6.98; CI, 17.67.

u-methyl-u- (2-piperidinoethyl) -1-naphthylacetic acid hydrochlorideM.P. 255-256" C. (crystallized from 95% ethanol).

Analysis.-For C H O NCI. Found, percent: C, 68.72; H, 7.43; N, 4.10; Cl,10.17. Calc., percent: C, 69.05; H, 7.53; N, 4.03; Cl, 10.19.

a-et-hyl-a-(2-piperidinoethyl)-1-naphthylacetic acid hydrochloride M.P.246247 C. (crystallized from ethanol).

Analysis.-For C H O NCI. Found, percent: C, 69.65; H, 7.73; N, 3.93; Cl,9.68. Calc., percent: C, 69.69; H, 7.80; N, 3.87; Cl, 9.80.

ez-isopropyl-u-(2-piperidinoethyl)-1-naphthylacetic acid hydrochloridea-Secbutyl-a-(2-piperidinoethyl)-1-naphthylacetic acid hydrochlorideM.P. 218-220 C. (decomp.) (crystallized from ethanol).

Analysis.-For C H O NCL Found, percent: C, 70.04; H, 8.10; N, 3.48;Cl,8.83. Calc., percent: C, 70.84; H, 8.27; N, 3.59; CI, 9.09.

e,x-di-(2-piperidinoethyl)-1-naphthylacetic acid dihydrochloride M.P.214.5-216 C. [crystallized from ethanol-ligroin (1:4)].

Analysis.For C H O N Cl Found, percent: C, 63.90; H, 7.94; N, 5.72; Cl,14.42. Calc., percent: C, 64.85; H, 7.96; N, 5.82; Cl, 14.73.

cc-Il'lethYl-oc- (Z-morpholinoethyl)-1-naphthylacetic acid hydrochlorideM.P. 245-246 C. (crystallized from 95% ethanol).

Analysis.-For C H O NCL Found, percent: C, 65.90; H, 7.09; N, 4.10; Cl,10.15. Calc., percent: C, 65.22; H, 6.91; N, 4.00; Cl, 10.14.

ot-ethyl-a-(2-morpholinoethyl)-1-naphthylacetic acid hydrochloride M.P.244-245" C. (crystallized from ethanol).

Analysis.-For C H O NCl. Found, percent: C, 65.70; H, 7.12; N, 3.88; Cl,9.56. Calc., percent: C, 66.01; H, 7.20; N, 3.85; Cl, 9.74.

a-isopropyl-a-(2-morpholinoethyl)-1-naphthylacetic acid hydrochlorideM.P. 203-204" C. (decomp.) [crystallized from ethanol-ligroin (1:1)].

Analysis.For C H O NCl. Found, percent: C, 66.11; H, 7.62; N, 3.76; Cl,9.19. Calc., percent: C, 66.74; H, 7.47; N, 3.71; Cl, 9.38.

a-sec.butyl-a-(2-rnorpholinoethyl)-1-naphthylacetic acid hydrochlorideM.P. 222 C. (decomp.) (crystallized from ethanol).

Analysis.For C H O NCI. Found, percent: C, 66.88; H, 7.84; N, 3.49; Cl,9.01. Calc., percent: C, 67.41; H, 7.72; N, 3.57; Cl, 9.05.

oc,oL-di- (2-morpholinoethyl) -1-naphthylacetic acid dihydrochlorideM.P. 22-223 C. (decomp.) (crysetallized from ethanol) Analysis.For C H ON Cl Found, percent: C,

7 58.85; H, 7.14; N, 5.72; CI, 14.35. Calc., percent: C, 59.38; H, 7.06;N, 5.77; CI, 14.61.

oc-is op I'OPYI-Ot- (2-diethylaminoethyl) l-naphthylacetic acid hydrochloride M.P. 195-196 C. (decomp.) (crystallized from isopropanol).

Analysis.--For CmHgoOgNCl- Found, percent: C, 69.84; H, 8.38; N, 3.93;Cl, 9.80. Calc., percent: C, 69.31; H, 8.31; N, 3.85; CI, 9.74.

Example 2 50 g. of a-(Z-morpholinoethyl)-l-naphthylacetonitrile arehydrolised by refluxing for 2 hours with a mixture of 65 ml. of 98%sulphuric acid, 65 ml. of acetic acid and 65 ml. of water. Aftercooling, the reaction mixture is diluted with 200 ml. of water andextracted twice with a total of 200 ml. of ether. The aqueous layer ismade alkaline to phenolphthalein with 30% sodium hydroxide, extractedtwice with ether and then acidified with 1:1 hydrochloric acid to a pHof 1. The aqueous acid solution is evaporated to dryness under reducedpressure and the residue four times extracted with a total of 800 ml. ofboiling ethanol. The ethanolic extracts are combined, evaporated todryness and the residue crystallized from 90% ethanol. Thea-(Z-morpholinoethyl)-1-naphthylacetic acid hydrochloride thus obtainedis a white crystalline solid melting at 261-262 C.

Analysis.-For C H O NCl. Found, percent: C, 64.16; H, 6.64; N, 4.15; Cl.10.23. Calc., percent: C. 64.37; H, 6.60; N, 4.17; Cl, 10.56.

The following compounds are obtained by a method analogous to thatdescribed above:

a-(Z-dimethylaminoethyl)-l-naphthylacctic acid hydrochloride M.P.226-227 C. (crystallized from ethanolzether).

Analysis.For C H O NCI. Found, percent: C, 65.30; H, 6.91; N, 4.79; Cl,11.83. Calc., percent: C, 65.41; H, 6.86; N, 4.77; Cl, 12.07.

a-'(2-diethylaminoethyl) -1-naphthylacetic acid hydrochloride M.P.207-208 C. (decomp.) [crystallized from ethanol isopropanol (1:1)]

Analysis.-Fr C H O NCI. Found, percent: C, 67.13; H 7.59; N, 4.29; 01,10.92. Calc., percent: 67.17; H, 7.52; N, 4.35; Cl, 11.02.

Example 3 40 g. of a-(2-piperidinoethyl)-l-naphthylacetonitrile arehydrolised (by a method analogous to that described in the previousexample) with a mixture of 52 m1. of 98% sulphuric acid, 52 ml. ofacetic acid and 52 ml. of water. After dilution with 100 ml. of waterand extraction with ether, the reaction mixture is made alkaline tophenophthalein with 50% sodium hydroxide. An oily mass is obtained whichis separated, washed with ether and then treated with cone. hydrochloricacid to a pH of 1. The oily layer is again separated, dissolved inisopropanol and dried over calcium chloride. After filtration withcharcoal, the solution is treated with ether and the precipitated tarrysolid is separated by filtration. The filtered compound is disintegratedwith acetone and then crystallized from isopropanol. Thea-(Z-piperidinoethyD- l-naphthylacetic acid hydrochloride thus obtainedis a white crystalline solid melting at 197199 C.

Analysis.For C H O NCI. Found, percent: C,

8 68.21; H, 7.22; N, 4.06; CI, 10.51. Calc., percent: C, 68.35; H, 7.24;N, 4.19; Cl, 10.62.

Example 4 A solution of sodium ethoxide obtained by dissolving 0.23 g.(0.01 atom) of sodium in 20 ml. of absolute ethanol is added to asuspension of 3.64 g. (0.01 mole) of e-ethyl-u-(2-morpholinoethyl)1-naphthylacetic acid hydrochloride in 20 ml. of absolute ethanol. Themixture is maintained, with stirring, at 40 C. for 1 hour. The suspendedsolid is then filtered off and washed with water to eliminate the sodiumchloride formed during the reaction. After crystallization from percentethanol, atethyl-a-(Z-morpholinoethyl)-l-naphthylacetic acid is obtainedas a colourless crystalline solid melting at 236- Example 5 A stream ofgaseous hydrochloric acid is slowly bubbled, for one and a half hoursand at room temperature, through an externally cooled solution of 40 g.of a-ethyltx-(3-dimethylam'inopropyl)-1-naphthylacetamide in 200 ml. ofglacial acetic acid. 50 ml. of freshly distilled isoamyl nitrite arethen added during 2 hours and with stirring. The bright red solutionthereby obtained is maintained for a further two hours at roomtemperature and then for 8 hours at C. The solvent is thereafterdistilled off from the reaction mixture at 50 C. at reduced pressure,the residue is disintegrated with ether and the solid thus formedcrystallized from ethanol. Theaethyl-u-(3-dimethylaminopropyl)-l-naphthylacetic acid hydrochloridethus obtained is a white crystalline solid melting at 251-252 C. withdecomp.

Analysis-For C19H25NO2C1. Found, percent: C, 67.67; H, 7.81; N, 4.15;Cl, 10.40. Calc., percent: C, 67.93; H, 7.80; N, 4.17; Cl, 10.52.

The following compounds are prepared by an analogous method:

u,a-di-(3-dimethylaminopropyl)-l-naphthylacetic acid dihydrochlorideM.P. 241-242 C. (decomp.) (crystallized from ethanol).

Analysis.For C H N O Cl Found, percent: C,

61.04; H, 7.94; N, 6.47; Cl, 16.38. Calc., percent: C,

61.53; H, 7.98; N, 6.53; CI, 16.51.

ot-isopropyl-a-(3-diethylaminopropyl)-l-naphthylacetic acidhydrochloride Example 6 A stream of gaseous hydrochloric acid is slowlybubbled, for one and a half hours and at room temperature, through anexternally cooled solution of 40 g. of u-isopropyla-(3-dimethylaminopropyl)-1-naphthylacetamide in 200 ml. of glacialacetic acid. 50 ml. of freshly distilled isoamyl nitrite are then addedduring 2 hours and with stirring. The bright red solution therebyobtained is maintained for a further 2 hours at room temperature and isthen refluxed for 14 hours.

The above procedure is repeated several times until a sample of thereaction mixture, after evaporation to dryness, yields a residue solublein 10% NaOH. This indicates completion of the reaction, and the productis separated as described in the previous example and crystallised fromethanol-ligroin (3:1). The a-isopropyl-a-(3-dimethylaminopropyl)-1-naphthylacetic acid hydrochloride thus obtainedis a white crystalline solid melting at 228-229 C. dec.

Arzalysis.-For C H NO CI. Found, percent: C, 67.98; H, 7.99; N, 4.06;Cl, 10.04. Calc., percent: C, 68.65; H, 8.07; N, 4.00; C], 10.13.

The following compounds are prepared by an analogous method:

a-isopropyl-ot- (3-pyrrolidinopropyl) 1 -naphthyl acetic acidhydro-chloride M.P. 172-173 C. decomp. (crystallised from acetone).

Analysis.-For C H NO Cl. Found, percent: C,-70.54; H, 8.11; N, 3.70; Cl,9.35. Calc., percent: C, 70.29; H, 8.05; N, 3.72; Cl, 9.43.

a-isopropyl-a-(3-pipenidinopropyl)-1-naphthylacetic acid hydrochlorideMP. 227-228 C. dec-omp. (crystallised from isopropanol) Analysis.For C HNO Cl. Found, percent: C, 70.91; H, 8.31; N, 3.61; Cl, 9.10. Calc.,percent: C, 70.84; H, 8.27; N, 3.59; Cl, 9.09.

a-isopropyhw (3 -morpholinopropyl) l-naphthylacetic acid hydrochlorideM.P. 226-227 C. decomp. (crystallised from ethanol).

Analysis-For C H NO Cl. Found, percent: C, 67.08; H, 7.80; N, 3.52; Cl,9.09. Calc. percent: C, 67.41; H, 7.72; N, 3.57; Cl, 9.05.

u-isopropyl-a-(4 dimethylaminobutyl)-1-naph-thylacetic acidhydrochloride Ml. 238-239 C. (crystallised from ethanolzligroin 3:2).

AnaZysis.For C H NO CL Found, percent: C, 68.94; H, 8.30; N, 3.76; Cl,9.77. Calc., percent: C, 69.31; H, 8.31; N, 3.85; Cl, 9.74.

u,u-di-(3-diethylaminopropyl)-naphthylacetic acid dihydrochloride M.P.231232 C. (decomp) (crystallised from isopropanol) Analysis.--For C H NO Cl Found, percent: C, 63.09; H, 8.83; N, 5.63; CI, 14.43. Calc.,percent: C, 64.31; H, 8.72; N, 5.77; Cl, 14.61.

Example 7 A solution of sodium ethoxide obtained by dissolving 0.23 g.(0.01 atom) of sodium in 20 ml. of absolute ethanol is added to asuspension of 3.35 g. (0.01 mole) ofa-ethyl-a-dimethylaminopropyl-l-naphthylacetic acid hydrochloride in 20ml. of absolute ethanol. The mixture is maintained, with stirring, at 40C. for 1 hour, then the suspended solid is separated by filtration andrepeatedly extracted with hot ethanol. The filtrate solution and thecombined ethanolic extracts are evaporated to dryness under reducedpressure and the residue is then crystallized from ethanol and driedunder vacuum at 100 C. The so obtainedot-ethyl-a-dimethylaminopropyl-l-naphthylacetic acid is a colourless andcrystalline solid which melts at 193-4194 C.

I claim:

1. ot-Methyl-ot-(2-morpholinoethyl) 1 naphthylacetic acid.

2. a-Isopropyl-a-(Z-diethylaminoethyl) 1 naphthylacetic acid.

3. a-Isopropyl-a-(Z-methylethylaminoethyl) 1 naphthylacetic acid.

10 4. A compound selected from the group consisting of a compound of theformula COOH | Rs-C-C HrCHr-X and a non-toxic salt thereof, wherein X isa member selected from the group consisting of morpholino, piperidinoand wherein R and R are alkyl of from 1 to 6 carbon atoms, and R isselected from the group consisting of alkyl of from 1 to 6 carbon atomsand CH CH X, wherein X has the same meaning as above.

5. A compound selected from the group consisting of a compound of theformula C O OH Br -(CH2) w-X and a non-toxic salt thereof, wherein X isa member selected from the group consisting of morpholino, piperidino,pyrrolidino and R4 wherein R and R are alkyl of from 1 to 6 carbonatoms, and n represents an integer of from 3 to 5; and R is selectedfrom the group' consisting of alkyl of from 1 to 6 carbon atoms and (CH),,X, wherein X and n have the same meaning as above.

6. A com'pound selected from the group consisting of a, a-di-(3-dimethylaminopropy1)-1 naphthylacetic acid and a, a-di(S-dimethylaminopropyl) 1 naphthy-lacetic acid.

7. A compound according to claim 4 which is a nontoxic acid additionsalt selected from the group consisting of a hydrochloride,hydr-obromide, sulphate, formate, acetate, citrate, 'tartrate, maleateand cyclohexyl sulphamate.

8. A compound according to claim 5 which is a nontoxic acid additionsalt selected from the group consisting of a hydrochloride,hydr-obromide, sulphate, formate, acetate, citrate, tartrate, maleate,cyclohexyl sulphamate, methanesulphamate and ethane disulphonate.

References Cited FOREIGN PATENTS 796,839 6/ 1958 Great Britain.

OTHER REFERENCES Casadio et 211.: Chemical Abstracts, vol. 59, pp. 1549-1550 (@1963), (effective date of abstract is 1962).

Martennson et al.: A.C.T.A. Chem. Scand., vol. 14, pp. 11-36-1 137,(1960).

NICHOLAS S. RIZZO, Primary Examiner.

ALEX MAZEL, JOSE TOVAR, Examiners.

